Nitroarylstannanes as synthons for the preparation of phenanthridine and benzo[i]phenanthridine derivatives

Full text of DOI:10.1021/jo991318g

2802
J . Org. Chem. 2000, 65, 2802-2805
Sch em e 1
Nitr oa r ylsta n n a n es a s Syn th on s for th e
P r ep a r a tion of P h en a n th r id in e a n d
Ben zo[i]p h en a n th r id in e Der iva tives
Dajie Li, Baoping Zhao, and Edmond J . LaVoie*
Department of Pharmaceutical Chemistry, Rutgers,
The State University of New J ersey,
Piscataway, New J ersey 08854-8020
Received August 19, 1999
Substituted benzo[c]phenanthridine alkaloids and,
more recently, benzacridine derivatives have demon-
strated activity as topoisomerase I poisons and were
shown to possess antitumor activity.1,2 In view of our
interest in furthering the structure activity associated
with these antitumor compounds, we explored synthetic
methods to provide for variously substituted phenanthri-
dine and benzo[i]phenanthridines. Preparation of the
N-oxide of phenanthridine has been accomplished by
reductive cyclization of 2-formyl-2′-nitrobiphenyl using
ferrous sulfate in aqueous ammonia.3 2-Formyl-3-(o-
nitrophenyl)thiophene, 2-formyl-3-(o-nitrophenyl)furan,
and 4-formyl-3-(o-nitrophenyl)thiophene have been simi-
larly treated to form thieno[2,3-c]quinoline-N-oxide, furo-
[2,3-c]quinoline-N-oxide, and thieno[3,4-c]quinoline-N-
oxide, respectively.3,4 A similar reductive cyclization has
recently been used in the preparation of 3-phenanthridin-
6-ylpropionic acid ethyl ester and its N-oxide.5 The
formation of the requisite 2-formyl-2′-nitroaryl interme-
diates was frequently accomplished by reaction of the
appropriate formyl boronic acid with o-nitrobenzene.3,4
3-Formyl-2-tributylstannaylfuran, however, has been
coupled to o-bromobenzene with subsequent reductive
cyclization to form furo[3,2-c]quinoline N-oxide.6 More
recently, coupling of 7-stannylated indoline with o-bromo-
benzaldehyde derivatives proved to be an effective method
for the preparation of pyrrolophenanthridone alkaloids.7
Using a similar approach, we envisioned that the use of
o-nitrostannanes could serve as an efficient method for
the preparation of a variety of substituted phenanthri-
dine and benzo[i]phenanthridine derivatives.
sis.8,9 However, only a limited number of o-nitroarylstan-
nanes have been synthesized,10 and there are no reports
of an o-nitrostannane being coupled with an o-bromoben-
zaldehyde derivative. In the present study, we investi-
gated the ease of formation of several o-nitroarylstan-
nanes (2a-f) with varying electron-donating and electron-
withdrawing substituents. We also evaluated these o-nitro-
arylstannanes for their utility in forming the requisite
2-(o-nitrophenyl)benzaldehyde and 2-(o-nitrophenyl)-1-
naphthaldehyde intermediates needed for the prepara-
tion of phenanthridine and benzo[i]phenanthridine de-
rivatives, respectively.
Various trimethyl-o-nitrophenylstannane derivatives
(2a -f) were synthesized from the appropriately substi-
tuted 2-bromonitrobenzene by reaction with hexameth-
ylditin and Pd(PPh3)4 in THF at reflux (Scheme 1) in
yields ranging from 55 to 75%.
Reaction of 2a , 2b, 2d , and 2f with 2-bromobenzalde-
hyde in the presence of tetrakis(triphenylphosphine)-
palladium(0) and cuprous bromide in refluxing THF
resulted in the formation of the 2-(o-nitrophenyl)benzal-
dehyde derivatives 3a , 3b, 3d , and 3f. Treatment of these
biphenyl derivatives with zinc dust in acetic acid provided
the phenanthridine derivatives, 4a , 4b, 4d , and 4f in
yields ranging from 55 to 83% (Scheme 2).
Compound 4d has previously been synthesized by
decomposition and subsequent rearrangement of 9-azido-
2-methoxyfluorene to provide a mixture of 4d together
with 8-methoxyphenanthridine in low yield.11 This same
method resulted in the formation of a mixture tentatively
characterized as 4e and 8-methylphenanthridine. An
alternative method for the preparation of 4e involved
reduction of 3-methyl-5H-phenanthridin-6-one with zinc
dust.12 There are several additional methods for the
preparation of phenanthridines.13 These methods, how-
ever, generally provide product in low yield and lack the
flexibility that would make them suitable for preparation
of many substituted phenanthridines. The coupling of
o-nitroarylstannanes to o-bromobenzaldehydes offers a
convenient route that allows for the preparation of a wide
variety of substituted phenanthridines.
The Stille coupling reaction for the formation of biaryl
compounds has been used extensively in organic synthe-
* To whom correspondence should be addressed. Tel:
(732) 445-2674. Fax: (732) 445-6312. E-mail: elavoie@rci.rutgers.edu.
(1) (a) J anin, Y. L.; Croisy, A.; Riou, J .-F.; Bisagni, E. J . Med. Chem.
1993, 36, 3686. (b) Gakunju, D. M. N.; Mberu, E. K.; Dossaji, S. F.;
Gray, A. I.; Waigh, R. D.; Waterman, P. G.; Watkins, W. M. Antimicrob.
Agents Chemother. 1995, 39, 2606. (c) Wang, L.-K.; J ohnson, R. K.;
Hecht, S. M. Chem. Res. Toxicol. 1993, 6, 813. (d) Arisawa, M.; Pezzuto,
J . M.; Bevelle, C.; Cordell, G. A. J . Nat. Prod. 1984, 47, 453. (e) Pezzuto,
J . M.; Antosiak, S. K.; Messmer, W. M.; Slaytor, M. B.; Honig, G. R.
Chem. Biol. Interact. 1983, 43, 323. (f) Wall, M. E.; Wani, M. C.; Taylor,
H. J . Nat. Prod. 1987, 50, 1095.
(2) (a) Makhey, D. B.; Yu, C.; Liu, A.; Liu, L. F.; LaVoie, E. J . Pro.
Am. Assoc. Cancer. Res. 1997, 38, 22 (b) Makhey, D. B.; Yu, C.; Liu,
A.; Liu, L. F.; LaVoie, E. J . Bioorg. Med. Chem. 2000, 8, in press.
(3) Gronowitz, S.; Ho¨rnfeldt, A.-B.; Yang, Y.-H. Chem. Scr. 1986,
26, 383.
(4) Yang, Y. Synth. Commun. 1989, 19, 1001.
(5) Pascal, C.; Gue´ritte-Voegelein, F.; Thal, C.; Gue´nard, D. Synth.
Commun. 1997, 27, 1501.
(8) Farina, V.; Krishnamurthy, V.; Scott, W. J . Org. React. 1997,
50, 3.
(9) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(10) (a) Kosugi, M.; Ohya, T.; Migita, T. Bull. Chem. Soc., J pn. 1983,
56, 3855. (b) Bumagin, N. A.; Gulevich, Y. V.; Beletskaya, I. P. Bull.
Acad. Sci USSR Div. Chem. Sci. 1984, 33, 1044 (c) Lundkvist, C.; Loc’h,
C.; Halldin, C.; Mathis, C.; Swahn, C.-G.; et al. J . Labelled Compd.
Radiopharm. 1997, 40, 586.
(6) Gronowitz, S.; Timari, G. J . Heterocycl. Chem. 1990, 27, 1159.
(7) Iwao, M.; Takehara, H.; Obata, S.; Wantanabe, M. Heterocycles
1994, 38, 1717.
(11) Arcus, C. L.; Coombs, M. M. J . Chem. Soc. 1954, 4319.
(12) Ritchie, E. J . Proc. R. Soc. N. S. Wales 1945, 78, 169.
10.1021/jo991318g CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/30/2000

Notes
J . Org. Chem., Vol. 65, No. 9, 2000 2803
Sch em e 2
Sch em e 3
should provide a practical method for the preparation of
benzo[i]phenanthridine derivatives.18
In summary, we have developed an effective method
for the preparation of 2-formyl-2′-nitrobiaryl derivatives
that can serve as effective intermediates for a variety of
substituted heterocycles that incorporate the phenan-
thridine ring system.
Exp er im en ta l Section
Gen er a l Meth od s. Proton (1H) and carbon (13C) nuclear
magnetic resonance were recorded using a 200 Fourier transform
1
spectrometer. NMR spectra (200 MHz H and 50 MHz 13C) are
reported with chemical shifts shown in δ units downfield from
tetramethylsilane (TMS). Coupling constants are reported in
hertz (Hz). Mass spectra were obtained from Washington
University Resource for Biomedical and Bio-organic Mass
Spectroscopy within the Department of Chemistry at Washing-
ton University, St. Louis, MO. Infrared spectral data (IR) are
reported in cm-1. Melting points were determined using a
capillary melting point apparatus and are uncorrected. Column
chromatography refers to flash chromatography conducted on
SiliTech 32-63 µm (ICN Biomedicals, Eschwegge, Ger.) using
the solvent system indicated. Compound 1a and 1b were
prepared by nitration of 4-bromoveratrole and 4-bromo-1,2-
(methylenedioxy)benzene as previously described.19,20 Intermedi-
ates 1c-f were purchased from Aldrich Chemical Co. (Milwau-
kee, WI). 2-Bromo-1-naphthaldehyde was prepared by treatment
of 2-bromo-3,4-dihydro-1-naphthaldehyde21 with DDQ. All reac-
tions were carried out under nitrogen.
2-Br om o-1-n a p h th a ld eh yd e. Dimethylformamide (0.8 mL,
10 mmol) was added dropwise to a solution of phosphorus
tribromide (0.8 mL, 8.4 mmol) in dry chloroform (20 mL) at 0
°C. The mixture was stirred at 0 °C for 1 h to give a pale yellow
suspension. A solution of â-tetralone (500 mg, 3.4 mmol) in dry
chloroform (20 mL) was added to the yellow suspension, and the
mixture was heated at reflux for 1 h. The reaction mixture was
cooled to 0 °C and made basic with saturated aqueous NaHCO3
solution. The resulting mixture was extracted with dichlo-
romethane, dried (anhyd Na2SO4), and evaporated in vacuo. The
residue was chromatographed over 100 g of silica gel using a
1:3 mixture of ethyl acetate/hexanes to give 2-bromo-3,4-dihydro-
1-naphthaldehyde in 83% yield.21 2-Bromo-3,4-dihydro-1-naph-
thaldehyde (160 mg, 0.68 mmol) and DDQ (154 mg, 0.68 mmol)
was refluxed in toluene (20 mL) for 12 h. After being cooled to
room temperature, the mixture was filtered through a Celite bed
and the filtrate was evaporated to dryness. The residue obtained
was chromatographed on 75 g silica gel using a 1:3 mixture of
ethyl acetate/hexanes to give 2-bromo-1-naphthaldehyde in 90%
yield: mp ) 80-2 °C; 1H NMR (CDCl3) δ 7.53-7.71 (3H, m),
7.85 (1H, dd, J ) 7.8, 1.5), 7.88 (1H, d, J ) 8.8), 9.10 (1H, d,
J ) 8.8), 10.77 (1H, s); 13C NMR (CDCl3) δ 125.2, 127.7, 128.9,
130.1, 131.0, 131.2, 132.2, 133.4, 135.8, 195.3; HRMS calcd for
This general synthetic approach was extended to the
preparation of several benzo[i]phenanthridine deriva-
tives. Reaction of 2a , 2c, or 2e with 2-bromo-1-naph-
thaldehyde provided a convenient route for the formation
of 2-(2-nitrophenyl)-1-naphthaldehydes 5a , 5c, and 5e,
respectively (Scheme 3). Treatment of these 2-(2-nitro-
phenyl)-1-naphthaldehydes with zinc dust in acetic acid
at reflux provided 8,9-dimethoxybenzo[i]phenanthridine
(6a ), benzo[i]phenanthridine (6c), and 8-methylbenzo[i]-
phenanthridine (6e) in good yield.
There are several methods for the preparation of
benzo[i]phenanthridine, 6c. These involve (1) the decom-
position and rearrangement of 11-azido-11H-benzo[a]-
fluorene,14 (2) reduction of benzo[i]phenanthridone,15
(3) benzyne cyclizations of either N-(2-chloro-1-nap-
hthylmethylene)aniline or N-phenyl-(2-chloro-1-naphthyl)-
methylamine,16 as well as (4) cyclization of N-[2-cyclo-
hexyl-1-(naphth-2-yl)]formamide followed by dehydroge-
nation with Pd/C.17 Compounds 6a and 6e have not been
previously synthesized. The use of 11-azido-11H-benzo-
[a]fluorene was shown to result in the formation of a
mixture of 6c and benzo[a]phenanthridine. The synthetic
methods for the preparation of either benzo[i]phenan-
thridone or N-[2-cyclohexyl-1-(naphth-2-yl)]formamide
are multistep and are not amenable to the synthesis of a
variety of substituted benzo[i]phenanthridines. It is not
surprising, therefore, that there are limited reports on
the synthesis of substituted benzo[i]phenanthridines in
the literature. The coupling of o-nitroarylstannanes with
appropriately substituted 2-bromo-1-naphthaldehydes
C
11H7BrO 233.9680, found 233.9682.
Gen er a l P r oced u r e for th e P r ep a r a tion of Tr im eth yln i-
(13) (a) Bolton, R.; Sosabowski, M. H. In Second Supplement to the
2nd Edition of Rodd’s Chemistry of Carbon Compounds; Sainsbury,
M., Ed.; Elsevier Science B.V.: New York, 1988; Vol. IV F/G, Chapter
28, pp 230-237. (b) Walls, L. P. In Heterocyclic Compounds; Elderfield,
R. C., Ed.; J ohn Wiley & Sons: New York, NY, 1952; Vol. 4, Chapter
4, pp 564-624. (c) Van Allan, J . A. In The Chemistry of Heterocyclic
Compounds; Allen, C. F. H., Ed.; Interscience Publishers: New York,
NY, 1958; Chapter IV, pp 271-319.
t r oa r ylst a n n a n es (2). Tr im et h yl(3,4-d im et h oxy-6-n it r o-
p h en yl)sta n n a n e (2a ). A mixture of hexamethylditin (3 g, 9.2
mmol), compound 1a (1.6 g, 6.1 mmol), and Pd(PPh3)4 (200 mg)
in anhydrous THF (30 mL) was heated to reflux under nitrogen
(14) Arcus, C. L.; Marks, R. E.; Coombs, M. M. J . Chem. Soc. 1957,
4064.
(18) Similar yields have been obtained using 1-acetyl-2-bromo-
naphthalene for the preparation of 5-methylbenzo[i]phenanthri-
dines.
(19) Pettit, G. R.; Piatak, D. M. J . Org. Chem. 25, 1960, 721
(20) Dallacker, F.; Wagner, A. Z. Naturforsch. 1984, 39b, 936.
(21) Gilchrist, T. L.; Summersell, R. J . J . Chem. Soc., Perkin Trans
I 1988, 2595.
(15) Badger, G. M.; Seidler, J . H. J . Chem. Soc. 1954, 2329.
(16) Kessar, S. V.; Dhillon, B. S.; J oshi, G. S. Indian J . Chem. 1973,
11, 624.
(17) Arumugam, N.; Krishnamurthi, S.; Shenbagamurthi, P.; Siva-
subramanian, S.; Raman, M. Indian J . Chem. 1974, 12, 664.

2804 J . Org. Chem., Vol. 65, No. 9, 2000
Notes
for 10 h. After the mixture was cooled to room temperature, THF
was evaporated and methylene chloride (30 mL) was added to
the residue. To this mixture was added dropwise aqueous
potassium fluoride (7.0 M, 2 mL) with vigorous stirring. The
mixture was passed through a Celite bed, and the filtrate was
washed with brine. The methylene chloride layer was dried
(anhyd Na2SO4), filtered, and evaporated in vacuo. The residue
was chromatographed over 100 g of silica gel using 1:6 ethyl
acetate/hexanes to give 2a in 70% yield: mp 115-7 °C; 1H NMR
129.0, 130.3, 130.7, 133.8, 134.1, 134.4, 141.0, 149.8, 160.3, 191.8;
HRMS calcd for C14H11NO4 - NO2 211.0759, found 211.0753.
2-(4-Tr iflu or om eth yl-2-n itr op h en yl)ben za ld eh yd e (3f).
Prepared from 2f (425 mg, 1.2 mmol) and 2-bromobenzaldehyde
(185 mg, 1.0 mmol) in 95% yield: mp ) 115-7 °C; 1H NMR
(CDCl3) δ 7.24 (1H, dd, J ) 6.7, 2.0), 7.47 (1H, d, J ) 8.1), 7.64-
7.69 (2H, m), 7.91 (1H, dd, J ) 8.1, 1.1), 7.97 (1H, d, J ) 6.7),
8.39 (1H, s), 9.87 (1H, s); 13C NMR (CDCl3) δ 120.6, 122.2, 122.3,
126.0, 129.7, 130.2, 132.0, 132.9, 133.4, 133.8, 134.4, 138.5, 148.9,
191.6; HRMS calcd for C14H8NO3F3 - NO2 249.0527, found
249.0531.
2-(3,4-Dim eth oxy-6-n itr op h en yl)-1-n a p h th a ld eh yd e (5a ).
Prepared from 2a (350 mg, 1.0 mmol) and 2-bromo-1-naphthal-
dehyde (235 mg, 1.0 mmol) in 90% yield: mp ) 136-8 °C; 1H
NMR (CDCl3) δ 3.94 (3H, s), 4.02 (3H, s), 6.74 (1H, s), 7.28 (1H,
d, J ) 8.4), 7.58-7.70 (2H, m), 7.78 (1H, s), 7.85-7.91 (1H, m),
8.04 (1H, d, J ) 8.4), 9.21 (1H, d, J ) 8.4), 10.24 (1H, s); 13C
NMR (CDCl3) δ 57.0, 57.1, 108.3, 114.8, 126.0, 127.1, 127.3,
128.4, 128.8, 129.4, 129.8, 130.7, 133.8, 134.7, 141.0, 145.5, 148.3,
153.1, 193.4; HRMS calcd for C19H15NO5 - NO2 291.1021, found
291.1012.
2-(o-Nitr op h en yl)-1-n a p h th a ld eh yd e (5c). Prepared from
2c (345 mg, 1.2 mmol) and 2-bromo-1-naphthaldehyde (235 mg,
1.0 mmol) in 97% yield: 1H NMR (CDCl3) δ 7.31 (1H, d, J )
8.4), 7.42 (1H, dd, J ) 7.0, 2.0), 7.60-7.79 (4H, m), 7.95 (1H,
dd, J ) 8.0, 1.3), 8.08 (1H, d, J ) 8.4), 8.18 (1H, dd, J ) 7.0,
2.0), 9.20 (1H, d, J ) 9.1), 10.28 (1H, s); 13C NMR (CDCl3) δ
125.2, 126.0, 127.2, 127.7, 128.8, 129.0, 129.9, 130.1, 131.1, 133.2,
133.7, 133.9, 134.7, 135.0, 144.2, 148.9, 193.1. HRMS calcd for
C17H11NO3 277.0739, found 277.0748.
2-(4-Meth yl-2-n itr op h en yl)-1-n a p h th a ld eh yd e (5e). Pre-
pared from 2e (300 mg, 1.0 mmol) and 2-bromo-1-naphthalde-
hyde (150 mg, 0.64 mmol) in 70% yield: 1H NMR (CDCl3) δ 2.55
(3H, s), 7.30 (1H, s), 7.43 (1H, d, J ) 7.8), 7.50 (1H, d, J ) 7.8),
7.57-7.78 (2H, m), 7.93 (1H, d, J ) 7.5), 7.98 (1H, s), 8.06 (1H,
d, J ) 8.4), 9.23 (1H, d, J ) 8.4), 10.26 (1H, s); 13C NMR (CDCl3)
δ 21.9, 125.5, 126.1, 127.4, 127.6, 129.0, 130.0, 131.1, 132.0,
133.5, 133.9, 134.0, 134.7, 140.7, 144.5, 148.8, 193.4; HRMS calcd
for C18H13NO3 - NO2 245.0966, found 245.0959.
Gen er a l P r oced u r e for th e P r ep a r a tion of P h en a n th r i-
d in e (4a ,b ,d ,f) a n d Ben zo[i]p h en a n t h r id in e Der iva t ives
(6a ,c,e). 2,3-Dim eth oxyp h en a n th r id in e (4a ). Compound 3a
(100 mg, 0.35 mmol) was dissolved in glacial acetic acid (20 mL)
and heated to reflux with zinc dust (200 mg, 3.1 mmol) for 3 h.
Acetic acid was evaporated in vacuo, and the residue was
dissolved in chloroform. The solution was filtered through a
Celite bed and the filtrate washed successively with saturated
sodium bicarbonate solution and brine. The organic layer was
dried (anhyd Na2SO4) and evaporated in vacuo. The residue was
chromatographed using 75 g of silica gel and a 1:1 mixture of
ethyl acetate/hexanes to give 4a in 55% yield: mp 127-9 °C;
1H NMR (CDCl3) δ 4.01(3H, s), 4.12 (3H, s), 7.59 (1H, s), 7.65
(1H, d, J ) 7.9), 7.80 (1H, dd, J ) 8.3, 1.4), 7.84 (1H, s), 8.02
(1H, d, J ) 7.7), 8.44 (1H, d, J ) 8.1), 9.17 (1H, s); 13C NMR
(CDCl3) δ 56.6, 102.2, 110.6, 118.8, 121.8, 126.2, 126.8, 129.3,
131.0, 132.6, 141.1, 150.0, 151.4, 151.9; IR (KBr) 1611, 1492,
1438; HRMS calcd for C15H13NO2 239.0947, found 239.0944.
2,3-Meth ylen ed ioxyp h en a n th r id in e (4b). Prepared from
3b (80 mg, 0.29 mmol) in 67% yield: mp ) 186-8 °C; 1H NMR
(CDCl3) δ 6.15 (2H, s), 7.54 (1H, s), 7.63 (1H, t, J ) 7.0), 7.80
(1H, t, J ) 7.0), 7.87 (1H, s), 7.98 (1H, d, J ) 8.0), 8.39 (1H, d,
J ) 8.0), 9.16 (1H, s); 13C NMR (CDCl3) δ 99.9, 102.3, 108.3,
120.6, 122.1, 126.2, 127.1, 129.1, 131.1, 133.0, 142.3, 148.7, 149.7,
151.8; IR (KBr) 1619, 1470; HRMS calcd for C14H9NO2 223.0633,
found 223.0633.
2
(CDCl3) δ 0.32 (9H, s [119Sn-H, d, J Sn-H ) 54]), 3.94 (3H, s),
3.99 (3H, s), 7.03 (1H, s), 7.88 (1H, s); 13C NMR (CDCl3) δ -7.2,
56.7, 107.7, 117.3, 134.0, 146.8, 149.8, 154.1; HRMS calcd for
C11H17NO4Sn - CH3 329.9937, found 329.9939.
T r im e t h y l(3,4-m e t h y le n e d io x y -6-n it r o p h e n y l)s t a n -
n a n e (2b). Prepared from 1b (1.6 g, 6.5 mmol) in 65% yield:
2
1H NMR (CDCl3) δ 0.32 (9H, s [119Sn-H, d, J Sn-H ) 52]), 6.12
(2H, s), 7.04 (1H, s), 7.82 (1H, s); 13C NMR (CDCl3) δ -6.9, 103.3,
105.8, 114.5, 137.2, 147.9, 149.4, 153.4; HRMS calcd for C10H13
-
NO4Sn - CH3 315.9632, found 315.9638.
Tr im eth yl(2-n itr op h en yl)sta n n a n e (2c). Prepared from 1c
(1.3 g, 6.4 mmol) in 75% yield: 1H NMR (CDCl3) δ 0.35 (9H, s
[
119Sn-H, d, 2J Sn-H ) 54]), 7.47-7.75 (3H, m), 8.34 (1H, dd, J )
8.1, 1.2); 13C NMR (CDCl3) δ -7.2, 124.5, 129.9, 134.0, 137.6,
140.3, 153.7; HRMS calcd for C9H13NO2Sn-CH3 271.9734, found
271.9744.
Tr im eth yl(4-m eth oxy-2-n itr op h en yl)sta n n a n e (2d ). Pre-
1
pared from 1d (1.6 g, 6.9 mmol) in 55% yield: mp 93-5 °C; H
NMR (CDCl3) δ 0.32 (9H, s [119Sn-H, d, 2J Sn-H ) 54]), 3.89 (3H,
s), 7.21 (1H, dd, J ) 8.0, 2.6), 7.57 (1H, d, J ) 8.0), 7.86 (1H, d,
J ) 2.6); 13C NMR (CDCl3) δ -7.1, 56.7, 107.7, 117.3, 133.9,
146.8, 149.6, 154.1; HRMS calcd for C10H15NO3Sn - CH3
301.9839, found 301.9832.
Tr im eth yl(4-m eth yl-2-n itr op h en yl)sta n n a n e (2e). Pre-
pared from 1e (1.1 g, 5.1 mmol) in 65% yield: 1H NMR (CDCl3)
2
δ 0.31 (9H, s [119Sn-H, d, J Sn-H ) 52]), 2.43 (3H, s), 7.43 (1H,
d, J ) 7.0), 7.56 (1H, d, J ) 7.0), 8.14 (1H, s); 13C NMR (CDCl3)
δ -7.3, 21.5, 124.9, 135.0, 136.5, 137.4, 140.4, 153.9; HRMS calcd
for C10H15NO2Sn - CH3 285.9890, found 285.9890.
Tr im eth yl(4-tr iflu or om eth yl-2-n itr oph en yl)stan n an e (2f).
Prepared from 1f (1.4 g, 5.2 mmol) in 60% yield: 1H NMR
2
(CDCl3) δ 0.38 (9H, s [119Sn-H, d, J Sn-H) 56]), 7.88 (2H, s),
8.58 (1H, s); 13C NMR (CDCl3) δ -7.1, 121.2, 126.3, 129.9, 132.8,
138.6, 145.7, 153.9; HRMS calcd for C10H12NO2F3Sn - CH3
339.9607, found 315.9604.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-F or m yl-2′-
n itr obip h en yl Der iva tives (3a ,b,d ,f) a n d 2-(2-Nitr op h en yl)-
1-n a p h th a ld eh yd es (5a ,c,e). 2-(4,5-Dim eth oxy-2-n itr op h e-
n yl)ben zaldeh yde (3a). Tetrakis(triphenylphosphine)palladium
(0) (60 mg, 0.05 mmol) and cuprous bromide (10 mg, 0.07 mmol)
were added to a solution of 2a (345 mg, 1.0 mmol) and
2-bromobenzaldehyde (150 mg, 0.8 mmol) in THF (15 mL) at
room temperature. The mixture was refluxed under N2 for 15
h. After cooling, THF was evaporated and ethyl acetate (30 mL)
was added to the residue. The solution was washed with water
(20 mL). The organic layer was separated and passed through
a Celite bed to remove suspended particles. The organic layer
was then washed with brine, dried (anhyd Na2SO4), and
evaporated in vacuo. The residue was chromatographed using
75 g of silica gel and a 1:3 mixture of ethyl acetate/hexanes to
1
give 3a in 70% yield: mp 118-120 °C; H NMR (CDCl3) δ 3.92
(3H, s), 4.03 (3H, s), 6.69 (1H, s), 7.24 (1H, dd, J ) 7.1, 1.9),
7.53-7.69 (2H, m), 7.75 (1H, s), 7.99 (1H, dd, J ) 7.1, 1.9), 9.86
(1H, s); 13C NMR (CDCl3) δ 56.9, 57.0, 108.2, 114.1, 128.9, 130.1,
130.2, 134.2, 141.3, 141.8, 149.1, 153.2, 191.7; HRMS calcd for
C15H13NO5 - NO2 241.0865, found 241.0855.
2-(4,5-Meth ylen edioxy-2-n itr oph en yl)ben zaldeh yde (3b).
Prepared from 2b (320 mg, 1.0 mmol) and 2-bromobenzaldehyde
(150 mg, 0.8 mmol) in 60% yield: 1H NMR (CDCl3) δ 6.18 (2H,
s), 6.70 (1H, s), 7.22 (1H, dd, J ) 6.9, 1.8), 7.30-7.36 (1H, m),
7.56-7.63 (1H, m), 7.65 (1H, s), 7.97 (1H, dd, J ) 7.0, 2.0), 9.89
(1H, s); 13C NMR (CDCl3) δ 103.8, 105.9, 111.5, 129.1, 130.1,
130.7, 131.1, 134.1, 134.3, 141.3, 142.7, 148.4, 151.9, 191.6.
2-(4-Meth oxy-2-n itr op h en yl)ben za ld eh yd e (3d ). Prepared
from 2d (300 mg, 1.0 mmol) and 2-bromobenzaldehyde (150 mg,
0.8 mmol) in 60% yield: 1H NMR (CDCl3) δ 3.94 (3H, s), 7.21-
7.27 (3H, m), 7.52-7.66 (3H, m), 7.98 (1H, dd, J ) 7.1, 2.0), 9.86
3-Meth oxyp h en a n th r id in e (4d ). Prepared from 3d (90 mg,
0.35 mmol) in 83% yield: mp ) 58-60 °C (lit.11 mp ) 57-8 °C);
1H NMR (CDCl3) δ 3.99 (3H, s), 7.31 (1H, dd, J ) 9.0, 2.7), 7.59-
7.66 (2H, m), 7.81 (1H, t, J ) 7.5), 8.01 (1H, d, J ) 7.7), 8.45
(1H, d, J ) 9.0), 8.49 (1H, d, J ) 8.1), 9.25 (1H, s); 13C NMR
(CDCl3) δ 56.0, 110.5, 118.6, 121.8, 123.9, 126.0, 126.9, 129.3,
131.5, 133.2, 146.6, 154.5, 155.3, 160.5; IR (KBr): 1673, 1611,
1467; HRMS calcd for C14H11NO 209.0841, found 209.0839.
3-Tr iflu or om eth ylp h en a n th r id in e (4f). Prepared from 3f
(100 mg, 0.34 mmol) in 60% yield: mp ) 120-2 °C; 1H NMR
(CDCl3) δ 7.76-7.97 (3H, m), 8.10 (1H, d, J ) 7.8), 8.47 (1H, s),
8.62 (1H, d, J ) 7.7), 8.66 (1H, d, J ) 8.5), 9.35 (1H, s); 13C
(1H, s); 13C NMR (CDCl3)
δ 56.5, 109.7, 119.7, 126.3,

Notes
J . Org. Chem., Vol. 65, No. 9, 2000 2805
NMR (CDCl3) δ 121.8, 122.7, 123.5, 123.8, 127.3, 127.4, 128.2,
129.2, 129.4, 131.0, 132.1, 132.2, 144.3, 155.4; IR (KBr) 1672,
1328; HRMS calcd for C14H8NF3 247.0609, found 247.0604.
8,9-Dim eth oxyben zo[i]ph en an th r idin e (6a). Prepared from
(DMSO) δ 2.60 (3H, s), 7.63 (1H, d, J ) 8.0), 7.72-7.89 (2H, m),
8.01 (1H, s), 8.18 (1H, d, J ) 7.5), 8.35 (1H, d, J ) 8.4), 8.79
(1H, d, J ) 7.5), 8.82 (1H, d, J ) 8.0), 9.16 (1H, d, J ) 8.0),
10.34 (1H, s); 13C NMR (DMSO) δ 21.4, 120.5, 121.2, 121.8, 122.8,
123.4, 127.4, 128.4, 129.1, 129.2, 129.4, 129.8, 131.7, 131.9, 132.3,
139.1, 145.4, 148.4; IR (KBr) 1651, 1614, 1589; HRMS calcd for
C18H13N 243.1048, found 243.1038.
1
5a (100 mg, 0.30 mmol) in 90% yield: mp 164-6 °C; H NMR
(CDCl3) δ 4.09 (3H, s), 4.14 (3H, s), 7.62 (1H, s), 7.65-7.76 (2H,
m), 7.84 (1H, s), 7.96 (1H, d, J ) 8.0), 8.09 (1H, d, J ) 8.0), 8.39
(1H, d, J ) 8.0), 8.87 (1H, d, J ) 8.0), 10.06 (1H, s); 13C NMR
(CDCl3) δ 56.6, 56.7, 102.0, 109.6, 119.4, 120.2, 121.4, 122.4,
127.2, 128.4, 129.4, 130.7, 131.6, 131.8, 141.1, 142.4, 146.0, 150.2,
151.6; IR (KBr) 1611, 1513, 1485; HRMS calcd for C19H15NO2
289.1103, found 289.1113.
Ack n ow led gm en t. Mass spectrometry was provided
by the Washington University Mass Spectrometry
Resource, an NIH Research Resource (Grant No.
P41RR0954). This study was supported by Grant CA
39662 from the National Cancer Institute (L.F.L.) and
a fellowship grant from the J ohnson & J ohnson Dis-
covery Research Fund (E.J .L.).
Ben zo[i]p h en a n th r id in e (6c). Prepared from 5c (80 mg.
0.29 mmol) in 95% yield: mp 180-2 °C (lit.14 mp ) 182 °C); 1H
NMR (DMSO) δ 7.75-7.94 (4H, m), 8.20 (1H, d, J ) 6.5), 8.24
(1H, d, J ) 6.5), 8.41 (1H, d, J ) 9.0), 8.90 (1H, d, J ) 9.0), 8.94
(1H, d, J ) 8.0), 9.20 (1H, d, J ) 8.0), 10.40 (1H, s); 13C NMR
(DMSO) δ 120.5, 121.6, 123.0, 123.7, 124.0, 127.5, 127.6, 128.5,
129.2, 129.3, 129.7, 129.9, 131.7, 132.1, 132.5, 145.2, 148.5; IR
(KBr) 1655, 1593, 1506; HRMS calcd for C17H11N 229.0891,
found 229.0895.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
8-Meth ylben zo[i]p h en a n th r id in e (6e). Prepared from 5e
(80 mg. 0.27 mmol) in 60% yield: mp ) 162-4 °C; 1H NMR
J O991318G